(+)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane, compositions and uses thereof

ABSTRACT

The present invention relates to (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane and pharmaceutically acceptable salts thereof, compositions comprising (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof, and methods for treating of or preventing relapse of depression, anxiety disorders, eating disorders, or urinary incontinence in a patient comprising administering (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof. The (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or pharmaceutically acceptable salt thereof is preferably substantially free of its corresponding (−)-enantiomer.

This application is the U.S. National Phase of PCT/US02/00845, filedJan. 11, 2002 and claims benefit to U.S. application Ser. No.09/758,883, filed on Jan. 11, 2001, now U.S. Pat. No. 6,372,919, issuedon Apr. 16, 2002, of which all are incorporated herein by reference intheir entirety.

1. FIELD OF THE INVENTION

The present invention relates to(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane and pharmaceuticalsalts thereof, compositions comprising(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof and methods for treating of orpreventing relapse of depression, anxiety disorders, eating disorders,or urinary incontinence in a patient comprising administering to apatient (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof.

2. BACKGROUND OF THE INVENTION

Depression is one of the most common of the mental illnesses, havingmorbidity rate of over 10% in the general population. Depression ischaracterized by feelings of intense sadness, despair, mental slowing,loss of concentration, pessimistic worry, agitation, andself-deprecation (Harrison's Principles of Internal Medicine 2490–2497(Fauci et al. eds., 14th ed. 1998)). Depression can have physicalmanifestations including insomnia, hypersomnia, anorexia, weight loss,overeating, decreased energy, decreased libido, and disruption of normalcircadian rhythms of activity, body temperature, and endosine functions.In fact, as many as 10% to 15% of depressed individuals display suicidalbehavior. R. J. Baldessarini, Drugs and the Treatment of PsychiatricDisorders: Depression and Mania, in Goodman and Gilman's ThePharmacological Basis of Therapeutics 431 (9^(th) ed. 1996).

U.S. Pat. No. 4,435,419 to Epstein et al. discloses racemic,(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane for use as ananti-depressant agent.

Administration of a racemic, i.e., 50:50, mixture of the (+)- and the(−)-enantiomer of any drug, for example(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, to a patient canbe disadvantageous. First, the racemic mixture might be lesspharmacologically active than one of its enantiomers, rendering racemicdrugs inherently inefficient. Second, the racemic mixture may be moretoxic to a patient than one of its enantiomers, so that administrationof a racemic mixture can lead to undesirable side effects in a patient.

Accordingly, there is a clear need in the art for an enantiomer of(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, the enantiomerbeing preferably substantially free of the corresponding oppositeenantiomer, which would overcome one or both of the aforementioneddisadvantages.

Citation of identification of any reference in Section 2 of thisapplication is not to be construed as an admission that such referenceis prior art to the present application.

3. SUMMARY OF THE INVENTION

In one embodiment, the invention provides(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane andpharmaceutically acceptable salts thereof.(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane andpharmaceutically acceptable salts thereof are useful for treating of orpreventing relapse of depression in a patient.

The present invention further provides compositions comprising aneffective amount of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexaneor a pharmaceutically acceptable salt thereof. The present compositionscan additionally comprise a pharmaceutically acceptable vehicle. Thesecompositions are useful for treating of or preventing relapse ofdepression in a patient.

In another embodiment, the invention provides a method for treating ofor preventing relapse of depression in a patient, comprisingadministering to a patient in need of such treatment or prevention aneffective amount of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexaneor a pharmaceutically acceptable salt thereof.

In still another embodiment, the invention provides a method fortreating of or preventing relapse of anxiety disorders, eatingdisorders, or urinary incontinence in a patient, comprisingadministering to a patient in need of such treatment or prevention aneffective amount of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexaneor a pharmaceutically acceptable salt thereof.

Preferably, (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof, particularly when used in thepresent methods or compositions, is substantially free of itscorresponding (−)-enantiomer,(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1 0]hexane. This enantiopuritycan be achieved through the use of chromatographic resolution techniquessuch as chiral chromatography or simulated moving bed technology, or viachemical separation through the employment of optically active resolvingagents.

The present invention may be understood more fully by reference to thedetailed description and examples, which are intended to exemplifynon-limiting embodiments of the invention.

4. DETAILED DESCRIPTION OF THE INVENTION

Applicants have discovered that(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane andpharmaceutically acceptable salts thereof are surprisingly andunexpectedly more active than(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane for treating of orpreventing relapse of depression in a patient.

4.1. DEFINITIONS

The term “substantially free of its corresponding (−)-enantiomer” meanscontaining no more than about 5% w/w of the corresponding(−)-enantiomer, preferably no more than about 2% w/w of thecorresponding (−)-enantiomer, more preferably no more than about 1% w/wof the corresponding (−)-enantiomer.

The term “corresponding (−)-enantiomer” when used in connection with(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof means“(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane” or apharmaceutically acceptable salt thereof.

A “patient” is an animal, including, but not limited to, an animal sucha cow; monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog,mouse, rat, rabbit, and guinea pig, and is more preferably a mammal, andmost preferably a human.

The phrase “pharmaceutically acceptable salt,” as used herein is a saltformed from an acid and the basic nitrogen group of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane. Preferred saltsinclude, but not limited, to sulfate, citrate, acetate, oxalate,chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, isonicotinate, acetate, lactate, salicylate, citrate, acidcitrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate,succinate, maleate, gentisinate, fumarate, gluconate, glucaronate,saccharate, formate, benzoate, glutamate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate(i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

4.2 (+)-1-(3,4-DICHLOROPHENYL)-3-AZABICYCLO[3.1.0]HEXANE

(+)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane, preferably thatsubstantially free of its corresponding (−)-enantiomer, can be obtainedfrom (±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane using chiralchromatographic methods, such as high-performance liquid chromatography(“HPLC”) with a suitable, preferably chiral, column(±)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane is obtainable usingmethods disclosed in U.S. Pat. No. 4,435,419 to Epstein et al.

In a preferred embodiment,(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane is obtained byresolving (±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane using achiral polysaccharide stationary phase and an organic eluent.Preferably, the polysaccharide is starch or a starch derivative.Advantageously, a chiral HPLC column can be used, for example, aCHIRALPAK AD column manufactured by Daicel and commercially availablefrom Chiral Technologies, Inc., Exton, Pa., more preferably a 1 cm×25 cmCHIRALPAK AD HPLC column. The preferred eluent is a hydrocarbon solventadjusted in polarity with a miscible polar organic solvent. Preferably,the organic eluent contains a non-polar, hydrocarbon solvent present inabout 95% to about 99.5% (volume/volume) and a polar organic solventpresent in about 5 to about 0.5% (volume/volume). In a preferredembodiment, the hydrocarbon solvent is hexane and the miscible polarorganic solvent is isopropylamine.

In another preferred embodiment, an alternative chromatographicprocedure, known as simulated moving bed (SMB) chromatography can beemployed for the resolution(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane. SMB isincreasingly becoming the method of choice for large-scale enantiomerseparation in the pharmaceutical industry (See Chemical and EngineeringNews, 2001, Vol. 79, No. 20, p 47).

In yet another preferred embodiment, the resolution of racemic(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane to obtain(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane may be achieved viathe use of optically active resolving acids via the formation of andsubsequent separation of the resulting diasteromeric salts. Commonlyemployed chiral acids for this purpose include: tartaric and O-acyltartaric acids, mandelic acid and O-substituted mandelic acids,1,1′-binaphthyl-2,2′-diyl hydrogen phosphate, camphoric acid, camphorsulfonic acid, and other readily-available optically active acids (bothcommercially available and readily synthesized).

For a general discussion of the separation of stereoisomers, see Elieland Wilen, STEREOCHEMISTRY OF ORGANIC COMPOUNDS; Wiley: New York 1994, p297–464, and references cited herein.

4.3. THERAPEUTIC USES OF(+)-1-(3,4-DICHLOROPHENYL)-3-AZABICYCLO[3.1.0]HEXANE

In accordance with the invention,(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof is administered to a patient,preferably a mammal, more preferably a human, for the treatment orprevention of disorders, including but not limited to, depression,anxiety disorders, eating disorders and urinary incontinence disorders.In one embodiment, “treatment” or “treating” refers to an ameliorationof such a disorder, or at least one discernible symptom thereof. Inanother embodiment, “treatment” or “treating” refers to an ameliorationof at least one measurable physical parameter, not necessarilydiscernible by the patient. In yet another embodiment, “treatment” or“treating” refers to inhibiting the progression of such a disorder,either physically, e.g., normalization of a discernible symptom,physiologically, e.g., normalization of a physical parameter, or both.In yet another embodiment, “treatment” or “treating” refers to delayingthe onset of such a disorder.

4.3.1 ALLEVIATION OF DEPRESSION USING(+)-1-(3,4-DICHLOROPHENYL)-3-AZABICYCLO[3.1.0]HEXANE

In certain embodiments,(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]-hexane or apharmaceutically acceptable salt thereof is administered to a patient,preferably a mammal, more preferably a human, as a preventative measureagainst relapse of depression. As used herein, “prevention” or“preventing” refers to a reduction of the risk of occurrence of relapsein a patient suffering from depression. In one embodiment,(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof is administered to a patient asa preventative measure against relapse. According to this embodiment,the patient can have a genetic predisposition to depression, such as afamily history of biochemical imbalance in the brain, or a non-geneticpredisposition to depression. Accordingly, the(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane andpharmaceutically acceptable salts thereof can be used for the treatmentof one manifestation of depression and prevention of another.

(+)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane andpharmaceutically acceptable salts thereof are also useful for treatingof or preventing relapse of endogenous depression, unipolar depression,retarded depression, agitated depression, bipolar depression,post-partum depression, depression with anxiety, depression withobsessiveness, depression with an illness causing seizures, dysthymia,seasonal affective disorder, diurnal mood variations, depressionassociated with menopause, and depression in association with medicalillness, alcohol, or substance abuse.

4.3.2 ALLEVIATION OF ANXIETY DISORDERS USING(+)-1-(3,4-DICHLOROPHENYL)-3-AZABICYCLO[3.1.0]HEXANE

(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane andpharmaceutically acceptable salts thereof are also useful for treatingof or preventing relapse of anxiety disorders (for an overview onanxiety disorders, see Derogatis L. R. & Wise, T. N., “Anxiety andDepressive Disorders in the Medical Patient,” Washington, D.C., AmericanPsychiatric Press, 1989, and references cited herein). Such disordersinclude, but are not limited to, Panic Disorder; Panic Attack;Agoraphobia; Generalized Anxiety Disorder; Obsessive-CompulsiveDisorders; Phobic Disorders and Post-Traumatic Stress Disorders, some ofwhich are further sub-classified as listed below.

Phobic-related Disorders include, but are not limited to, specificphobias, such as Acrophobia, Algophobia, Arachnophobia, Astraphobia,Aviaphobia, Claustrophobia, Cynophobia, Demophobia, Hematophobia,Monophobia, Nyctophobia, Pathophobia, Pyrophobia, Thanatophobia andZoophobia; General Social Phobia; Specific Social Phobia and PhobicDisorder not otherwise specified (NOS).

Obsessive-Compulsive-related Disorders include, but are not limited to,Trichotillomania, Body Dysmorphic Disorder, Habit Disorders, TicDisorders; Tourette's Syndrome and Obsessive-Compulsive Disorder nototherwise specified (NOS).

Post-traumatic-related Disorders include, but are not limited to, AcuteStress Disorder; and Post-Traumatic Disorder not otherwise specified(NOS).

4.3.3 OTHER DISORDERS ALLEVIATED USING(+)-1-(3,4-DICHLOROPHENYL)-3-AZABICYCLO[3.1.0]HEXANE

Disorders alleviated through the use of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane also include eatingdisorders and urinary incontinence and are not limited to the specificdisorders described herein, as many types of disorders may manifest froma particular primary disorder. For example, as disclosed in U.S. Pat.No. 6,132,724 to Blum, attention deficit hyperactivity disorder maymanifest itself in the form of alcohol abuse, drug abuse, obsessivecompulsive behaviors, learning disorders, reading problems, gambling,manic symptoms, phobias, panic attacks, oppositional defiant behavior,conduct disorder, academic problems in school, smoking, abnormal sexualbehaviors, schizoid behaviors, somatization, depression, sleepdisorders, general anxiety, stuttering, and tics disorders.Additionally, clinical terms used herein for many specific disorders arefound in the Quick Reference to the Diagnostic Criteria From DSM-IV(Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition),The American Psychiatric Association, Washington, D.C., 1994, 358 pages.Specific disorders related to the indicated disorders can be found inthis reference. In addition, a detailed discussion of eating disorderscan be found in . . . For further discussion on urinary incontinence andrelated conditions, see

Eating disorders include, but are not limited to, Anorexia Nervosa;Binge-Eating Disorder; Bulimia Nervosa, Nonpurging Type; BulimiaNervosa, Purging Type; and Eating Disorder not otherwise specified(NOS).

Urinary incontinence includes, but is not limited to, Urge Incontinence;Stress Incontinence; Overflow Incontinence; Functional Incontinence;Neurogenic Incontinence and Post-Prostatectomy Incontinence.

4.4. THERAPEUTIC/PROGHYLACTIC ADMINISTRATION AND COMPOSITION OF THEINVENTION

Due to their activity,(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane andpharmaceutically acceptable salts thereof are advantageously useful inveterinary and human medicine. As described above,(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane andpharmaceutically acceptable salts thereof are useful for the treatmentof or prevention of relapse of depression, anxiety disorders, eatingdisorders and urinary incontinence-related disorders in a patient.

When administered to a patient,(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof is preferably administered ascomponent of a composition that optionally comprises a pharmaceuticallyacceptable vehicle. The present compositions, which comprise(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof, are preferably administeredorally. The compositions of the invention may also be administered byany other convenient route, for example, by infusion or bolus injection,by absorption through epithelial or mucocutaneous linings (e.g., oralmucosa, rectal, and intestinal mucosa, etc.) and may be administeredtogether with another biologically active agent. Administration can besystemic or local. Various delivery systems are known, e.g.,encapsulation in liposomes, microparticles, microcapsules, capsules,etc., and can be used to administer(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane andpharmaceutically acceptable salts thereof.

In certain embodiments, the present compositions can comprise(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane and/or one or morepharmaceutically acceptable salts thereof.

Methods of administration include but are not limited to intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, sublingual, intranasal, intracerebral, intravaginal,transdermal, rectally, by inhalation, or topically, particularly to theears, nose, eyes, or skin. The mode of administration is left to thediscretion of the practitioner. In most instances, administration willresult in the release of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof into the bloodstream.

In specific embodiments, it may be desirable to administer(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof locally. This may be achieved,for example, and not by way of limitation, by local infusion duringsurgery, topical application, e.g., in conjunction with a wound dressingafter surgery, by injection, by means of a catheter, by means of asuppository, or by means of an implant, said implant being of a porous,non-porous, or gelatinous material, including membranes, such assialastic membranes, or fibers.

In certain embodiments, it may be desirable to introduce(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof into the central nervous systemby any suitable route, including intraventricular, intrathecal andepidural injection. Intraventricular injection may be facilitated by anintraventricular catheter, for example, attached to a reservoir, such asan Ommaya reservoir.

Pulmonary administration can also be employed, e.g., by use of aninhaler or nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. Incertain embodiments,(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane andpharmaceutically acceptable salts thereof can be formulated as asuppository, with traditional binders and vehicles such astriglycerides.

In another embodiment,(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane andpharmaceutically acceptable salts thereof can be delivered in a vesicle,in particular a liposome (see Langer, 1990, Science 249:1527–1533; Treatet al., in Liposomes in the Therapy of Infectious Disease and Cancer,Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353–365 (1989);Lopez-Berestein, ibid., pp. 317–327; see generally ibid.).

In yet another embodiment,(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane andpharmaceutically acceptable salts thereof can be delivered in acontrolled release system (see, e.g., Goodson, in Medical Applicationsof Controlled Release, supra, vol. 2, pp. 115–138 (1984)). Othercontrolled-release systems discussed in the review by Langer, 1990,Science 249:1527–1533) may be used. In one embodiment, a pump may beused (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng.14:201; Buchwald et al., 1980, Surgery 88:507 Saudek et al., 1989, N.Engl. J. Med. 321:574). In another embodiment, polymeric materials canbe used (see Medical Applications of Controlled Release, Langer and Wise(eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled DrugBioavailability, Drug Product Design and Performance, Smolen and Ball(eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J. Macromol.Sci. Rev. Macromol. Chem. 23:61; see also Levy et al., 1985, Science228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989,J. Neurosurg. 71:105). In yet another embodiment, a controlled-releasesystem can be placed in proximity of a target of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof, e.g., the spinal column orbrain, thus requiring only a fraction of the systemic dose.

The present compositions can optionally comprise a suitable amount of apharmaceutically acceptable vehicle so as to provide the form for properadministration to the patient.

In a specific embodiment, the term “pharmaceutically acceptable” meansapproved by a regulatory agency of the Federal or a state government orlisted in the U.S. Pharmacopeia or other generally recognizedpharmacopeia for use in animals, mammals, and more particularly inhumans. The term “vehicle” refers to a diluent, adjuvant, excipient, orcarrier with which a compound of the invention is administered. Suchpharmaceutical vehicles can be liquids, such as water and oils,including those of petroleum, animal, vegetable or synthetic origin,such as peanut oil, soybean oil, mineral oil, sesame oil and the like.The pharmaceutical vehicles can be saline, gum acacia, gelatin, starchpaste, talc, keratin, colloidal silica, urea, and the like. In addition,auxiliary, stabilizing, thickening, lubricating and coloring agents maybe used. When administered to a patient, the pharmaceutically acceptablevehicles are preferably sterile. Water is a preferred vehicle when thecompound of the invention is administered intravenously. Salinesolutions and aqueous dextrose and glycerol solutions can also beemployed as liquid vehicles, particularly for injectable solutions.Suitable pharmaceutical vehicles also include excipients such as starch,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, sodium stearate, glycerol monostearate, talc, sodium chloride,dried skim milk, glycerol, propylene, glycol, water, ethanol and thelike. The present compositions, if desired, can also contain minoramounts of wetting or emulsifying agents, or pH buffering agents.

The present compositions can take the form of solutions, suspensions,emulsion, tablets, pills, pellets, capsules, capsules containingliquids, powders, sustained-release formulations, suppositories,emulsions, aerosols, sprays, suspensions, or any other form suitable foruse. In one embodiment, the pharmaceutically acceptable vehicle is acapsule (see e.g., U.S. Pat. No. 5,698,155). Other examples of suitablepharmaceutical vehicles are described in Remington's PharmaceuticalSciences, Alfonso R. Gennaro ed., Mack Publishing Co. Easton, Pa., 19thed., 1995, pp. 1447 to 1676, incorporated herein by reference.

In a preferred embodiment,(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof is formulated in accordancewith routine procedures as a pharmaceutical composition adapted for oraladministration to human beings. Compositions for oral delivery may be inthe form of tablets, lozenges, aqueous or oily suspensions, granules,powders, emulsions, capsules, syrups, or elixirs, for example. Orallyadministered compositions may contain one or more agents, for example,sweetening agents such as fructose, aspartame or saccharin; flavoringagents such as peppermint, oil of wintergreen, or cherry; coloringagents; and preserving agents, to provide a pharmaceutically palatablepreparation. Moreover, where in tablet or pill form, the compositionscan be coated to delay disintegration and absorption in thegastrointestinal tract thereby providing a sustained action over anextended period of time. Selectively permeable membranes surrounding anosmotically active driving compound are also suitable for orallyadministered compositions. In these later platforms, fluid from theenvironment surrounding the capsule is imbibed by the driving compound,which swells to displace the agent or agent composition through anaperture. These delivery platforms can provide an essentially zero orderdelivery profile as opposed to the spiked profiles of immediate releaseformulations. A time delay material such as glycerol monostearate orglycerol stearate may also be used. Oral compositions can includestandard vehicles such as mannitol, lactose, starch, magnesium stearate,sodium saccharin, cellulose and magnesium carbonate. Such vehicles arepreferably of pharmaceutical grade. Typically, compositions forintravenous administration comprise sterile isotonic aqueous buffer.Where necessary, the compositions may also include a solubilizing agent.

In another embodiment,(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof can be formulated forintravenous administration. Compositions for intravenous administrationmay optionally include a local anesthetic such as lignocaine to lessenpain at the site of the injection. Generally, the ingredients aresupplied either separately or mixed together in unit dosage form, forexample, as a dry lyophilized powder or water free concentrate in ahermetically sealed container such as an ampoule or sachette indicatingthe quantity of active agent. Where(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof is to be administered byinfusion, it can be dispensed, for example, with an infusion bottlecontaining sterile pharmaceutical grade water or saline. Where the(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof is administered by injection,an ampoule of sterile water for injection or saline can be provided sothat the ingredients may be mixed prior to administration.

The amount of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof that will be effective in thetreatment of a particular depression disorder, anxiety disorder, eatingdisorder or urinary incontinence related disorder, will depend on thenature of the disorder or condition, and can be determined by standardclinical techniques. In addition, in vitro or in vivo assays mayoptionally be employed to help identify optimal dosage ranges. Theprecise dose to be employed will also depend on the route ofadministration, and the seriousness of the disease or disorder, andshould be decided according to the judgment of the practitioner and eachpatient's circumstances. However, suitable dosage ranges for oraladministration are generally about 0.2 milligram to about 2.0 milligramsof (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.10]hexane or apharmaceutically acceptable salt thereof per kilogram body weight perday. In specific preferred embodiments of the invention, the oral doseis about 0.01 milligram to about 100 milligrams per kilogram body weightper day, more preferably about 0.1 milligram to about 75 milligrams perkilogram body weight per day, more preferably about 0.5 milligram toabout 50 milligrams per kilogram body weight per day, and yet morepreferably about 1 milligram to about 30 milligrams per kilogram bodyweight per day. In another preferred embodiment, the oral dose is about1 milligram to about 3 milligrams of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof of the invention per kilogrambody weight per day. The dosage amounts described herein refer to totalamounts administered; that is, if(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane and/or one or morepharmaceutically acceptable salts thereof are administered, thepreferred dosages correspond to the total amount administered. Oralcompositions preferably contain about 10% to about 95% active ingredientby weight.

Suitable dosage ranges for intravenous (i.v.) administration are about0.01 milligram to about 100 milligrams per kilogram body weight per day,about 0.1 milligram to about 35 milligrams per kilogram body weight perday, and about 1 milligram to about 10 milligrams per kilogram bodyweight per day. Suitable dosage ranges for intranasal administration aregenerally about 0.01 pg/kg body weight per day to about 1 mg/kg bodyweight per day. Suppositories generally contain about 0.01 milligram toabout 50 milligrams of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof per kilogram body weight perday and comprise active ingredient in the range of about 0.5% to about10% by weight.

Recommended dosages for intradermal, intramuscular, intraperitoneal,subcutaneous, epidural, sublingual, intracerebral, intravaginal,transdermal administration or administration by inhalation are in therange of about 0.001 milligram to about 200 milligrams per kilogram ofbody weight per day. Suitable doses for topical administration are inthe range of about 0.001 milligram to about 1 milligram, depending onthe area of administration. Effective doses may be extrapolated fromdose-response curves derived from in vitro or animal model test systems.Such animal models and systems are well known in the art.

The invention also provides pharmaceutical packs or kits comprising oneor more vessels containing(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof. Optionally associated withsuch container(s) can be a notice in the form prescribed by agovernmental agency regulating the manufacture, use or sale ofpharmaceuticals or biological products, which notice reflects approvalby the agency of manufacture, use or sale for human administration. In acertain embodiment, the kit contains(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane and/or one or morepharmaceutically acceptable salts thereof. In another embodiment, thekit comprises a therapeutic agent and(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof.

(+)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane andpharmaceutically acceptable salts thereof are preferably assayed invitro or in vivo, for the desired therapeutic or prophylactic activity,prior to use in humans. For example, in vitro assays can be used todetermine whether it is preferable to administer(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, a pharmaceuticallyacceptable salt thereof, and/or another therapeutic agent. Animal modelsystems can be used to demonstrate safety and efficacy.

Other methods will be known to the skilled artisan and are within thescope of the invention.

4.5. COMBINATION THERAPY

In certain embodiments of the present invention,(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof can be used in combinationtherapy with at least one other therapeutic agent.(+)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof and the other therapeutic agentcan act additively or, more preferably, synergistically. In a preferredembodiment, a composition comprising(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof is administered concurrentlywith the administration of another therapeutic agent, which can be partof the same composition as or in a different composition from thatcomprising (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof. In another embodiment, acomposition comprising(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof is administered prior orsubsequent to administration of another therapeutic agent. As many ofthe disorders for which(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane andpharmaceutically acceptable salts thereof are useful in treating arechronic, in one embodiment combination therapy involves alternatingbetween administering a composition comprising a(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof and a composition comprisinganother therapeutic agent. The duration of administration of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, a pharmaceuticallyacceptable salt thereof, or the other therapeutic agent can be, e.g.,one month, three months, six months, a year, or for more extendedperiods, such as the patient's lifetime. In certain embodiments, when acomposition of the invention is administered concurrently with anothertherapeutic agent that potentially produces adverse side effectsincluding, but not limited to, toxicity, the other therapeutic agent canadvantageously be administered at a dose that falls below the thresholdat which the adverse side effect is elicited.

The other therapeutic agent can be an anti-depressant agent. Usefulanti-depressant agents include, but are not limited to, amitriptyline,clomipramine, doxepine, imipramine, trimipramine, amoxapine,desipramine, maprotiline, nortriptyline, protripyline, fluoxetine,fluvoxamine, paroxetine, setraline, venlafaxine, bupropion, nefazodone,trazodone, pheuelzine, tranylcypromine and selegiline.

The other therapeutic agent can be an anxiolytic agent. Usefulanxiolytic agents include, but are not limited to, benzodiazepines, suchas alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam,halazepam, lorazepam, oxazepam, and prazepam; non-benzodiazepine agents,such as buspirone; and tranquilizers, such as barbituates.

The other therapeutic agent can be an antipsychotic drug. Usefulantipsychotic drugs include, but are not limited to, phenothiazines,such as chlorpromazine, mesoridazine besylate, thioridazine,acetophenazine maleate, fluphenazine, perphenazine, and trifluoperazine;thioxanthenes, such as chlorprothixene, and thiothixene; and otherhetercyclic compounds, such as clozapine, haloperidol, loxapine,molindone, pimozide, and risperidone. Preferable anti-psychotic drugsinclude chlorpromazine HCl, thioridazine HCl, fluphenazine HCl,thiothixene HCl, and molindone HCl.

The other therapeutic agent can be an anti-obesity drug. Anti-obesitydrugs for use in combination with the compounds of the inventioninclude, but are not limited, to β-adrenergic receptor agonists,preferably β-3 receptor agonists: fenfluramine; dexfenfluramine;sibutramine; bupropion; fluoxetine; phentermine; amphetamine;methamphetamine; dextroamphetamine; benzphetamine; phendimetrazine;phenmetrazine; diethylpropion; mazindol; and phenylpropanolamine.

5. EXAMPLE (+)-1-(3,4-DICHLOROPHENYL)-3-AZABICYCLO[3.1.0]HEXANE 5.1RESOLUTION OF THE RACEMATE VIA CHIRAL CHROMATOGRAPHY

To 279 mg of (±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexanehydrochloride obtained using the methods described in Epstein et al., J.Med. Chem., 24:481–490 (1981) was added 7 mL of 9:1 hexane:isopropylalcohol, followed by 8 drops of diethylamine. To the resulting mixturewas added isopropyl alcohol, dropwise, until a solution was obtained.The solution was concentrated to a volume of 6 mL using a stream ofhelium gas, and six 1-mL portions of the concentrate were subjected tohigh-performance liquid chromatography using an HPLC instrument equippedwith a 1 cm×25 cm Daicel CHIRALPAK AD column (Chiral Technologies, Inc.,Exton, Pa.). Elution was carried out at ambient temperature using 95:5(v/v) hexane:isopropyl alcohol solution containing 0.05% diethylamine asa mobile phase at a flow rate of 6 mL/min. The fraction eluting at about21.5 to 26 minutes was collected and concentrated to provide a firstresidue, which was dissolved in a minimal amount of ethyl acetate. Usinga stream of nitrogen, the ethyl acetate solution was evaporated toprovide a second residue, which was dissolved in 1 mL of diethyl ether.To the diethyl ether solution was added 1 mL diethyl ether saturatedwith gaseous hydrochloric acid. A colorless precipitate formed, whichwas filtered, washed with 2 mL of diethyl ether and dried to provide73.4 mg of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexanehydrochloride: optical rotation [α]²⁵ _(D)=+60° in methanol at 2 mg/mL;99.7% enantiomeric excess.

5.2 RESOLUTION OF THE RACEMATE VIA THE USE OF L-DI-(O-BENZOYL) TARTARICACID AS A CHIRAL RESOLVING AGENT

A 2.68 g (0.0101 mol) sample of(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride asdescribed in Epstein, et al., J. Med. Chem., 1981, 24, pp. 481–490, wasdissolved in 50 mL of water and this solution was made basic to pH 11with 10N sodium hydroxide solution, and the precipitated free base wasextracted into 25 mL of dichloromethane. This solution was dried oversodium sulfate and filtered. To this filtrate, was added a solution of3.70 g (0.1030 mol) of L-di-(O-benzoyl)tartaric acid in 25 mL ofmethanol, and this solution was boiled until crystallization ensued. Themixture was cooled to room temperature and allowed to stand for onehour. The crystals were collected to give 3.21 g of colorless crystalswhich were boiled in 50 mL of methanol, and this mixture was cooled inan ice bath, then filtered to give 2.04 g of colorless crystals, m.p.185–187° C. of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexanemonosalt with L-di-(O-benzoyl) tartaric acid. This salt was stirred with5N aqueous sodium hydroxide and the liberated free base was extractedinto ethyl acetate. The organic layer was washed with dilute aqueoussodium hydroxide solution, then water, and then dried over sodiumsulfate. This was filtered, and the filtrate was treated with a solutionof HCl in ether until precipitation ceased. The crystals were collectedby filtration and air dried to yield 0.748 g of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride ascolorless crystals, m.p. 173–173° C., (α)=+64.2°, C=6.7, MeOH, which wassubstantially free of the corresponding (−)-enantiomer.

6. EXAMPLE ACTIVITY COMPARISON OF(+)-1-(3,4-DICHLOROPHENYL)-3-AZABICYCLO[3.1.0]HEXANE AND(±)-1-(3,4-DICHLOROPHENYL)-3-AZABICYCLO[3.1.0]HEXANE 6.1. NOREPINEPHRINETRANSPORTER BINDING ASSAY

The anti-depressant properties of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride werecompared to the antidepressant properties of(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride usinga standard norepinephrine transporter binding assay.

6.1.1. MATERIALS AND METHODS

The norepinephrine binding assay was performed according to the methodsdescribed in Raisman et al., Eur. J. Pharmacol. 78:345–351 (1982) andLanger et al., Eur. J. Pharmacol. 72:423 (1981). The receptor source wasrat forebrain membranes; the radioligand was [³H]-nisoxetine (60–85Ci/mmol) at a final ligand concentration of 1.0 nM; the non-specificdeterminant [1.0 μm]; reference compound and positive control were(±)-desmethylimipramine HCl.(+)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl was obtainedaccording to the method of Example 5, above. Reactions were carried outin 50 mM TRIS-HCl (pH 7.4), containing 300 mM NaCl and 5 mM KCl at 0° C.to 4° C. for 4 hours. The reaction was terminated by rapid vacuumfiltration onto glass fiber filters. Radioactivity trapped in thefilters was determined and compared to control values in order toascertain the interactions of the test compound with the norepinephrineuptake site. The data are reported in Table 1 below.

6.1.2. RESULTS

TABLE 1 Norepinephrine Transporter Binding Assay Compound Ki(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl 1.42 × 10⁻⁷(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl 8.20 × 10⁻⁸(±)-desmethylimiprimine HCl 1.13 × 10⁻⁹

The data in Table 1 show that(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl has asignificantly greater affinity for the norepinephrine uptake site thandoes the (±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl.Successful inhibition of norepinephrine reuptake has been has beenassociated with the treatment of one or more of the symptoms ofdepression (R. J. Baldessarini, Drugs and the Treatment of PsychiatricDisorders: Depression and Mania, in Goodman & Gilman's ThePharmacological Basis of Therapeutics 431–459 (9^(th) ed. 1996)).Therefore, (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof will be significantly moreactive than (±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof for treating of or preventingrelapse of depression in a patient.

6.2. SEROTONIN TRANSPORTER BINDING ASSAY

The anti-depressant properties of(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride werecompared to the anti-depressant properties of(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0] hexane hydrochlorideusing a standard serotonin transporter binding assay.

6.2.1. MATERIALS AND METHODS

The serotonin binding assay was performed according to the methodsdescribed in D'Amato et al., J. Pharmacol. Exp. Ther. 242:364–371 (1987)and Brown et al., Eur. J. Pharmac. 123:161–165 (1986). The receptorsource was rat forebrain membranes; the radioligand was [³H]-citalopram(70–87 Ci/mmol) with a final ligand concentration of 0.7 nM; thenon-specific determinant was clomipramine [10 μm]; and the referencecompound and positive control were (±)-desmethylimipramine.(+)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl was obtainedaccording to the method of Example 5, above. Reactions were carried outin 50 mM TRIS-HCl (pH 7.4) containing 120 mM NaCl and 5 mM KCl at 25° C.for 60 minutes. The reaction was terminated by rapid vacuum filtrationonto glass fiber filters. Radioactivity trapped in the filters wasdetermined using liquid scintillation spectrometry and compared tocontrol values in order to ascertain any interactions of test compoundwith the serotonin transporter binding site. The data are reported inTable 2 below.

6.2.2 RESULTS

TABLE 2 Serotonin Transporter Binding Assay Compound Ki(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl 1.18 × 10⁻⁷(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl 5.08 × 10⁻⁸(±)-desmethylimipramine HCl 2.64 × 10⁻⁸

The data in Table 2 show that(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl has asignificantly greater affinity for the serotonin uptake site than does(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl. Successfulinhibition of serotonin reuptake has been has been associated with thetreatment of one or more of the symptoms of depression (R. J.Baldessarini, Drugs and the Treatment of Psychiatric Disorders:Depression and Mania, in Goodman & Gilman's The Pharmacological Basis ofTherapeutics 431–459 (9^(th) ed. 1996)). Therefore,(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof will be significantly moreactive than (±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutical salt thereof for treating of or preventing relapse ofdepression in a patient.

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodiments thatare functionally equivalent are within the scope of this invention.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in theart and are intended to fall within the scope of the appended claims.

A number of references have been cited, the entire disclosures of whichare incorporated herein by reference.

1. A method for treating an anxiety disorder in a patient, comprisingadministering to a patient in need of such treatment an effective amountof (+)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof, each being substantially freeof its corresponding (−)-enantiomer.
 2. The method according to claim 1,wherein (+)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane orpharmaceutically acceptable salt thereof has no more than about 2% w/wof the corresponding (−)-enantiomer.
 3. The method according to claim 1,wherein the (+)-1-(3,4Dichlorophenyl)-3-azabicyclo[3.1.0]hexane orpharmaceutically acceptable salt thereof has no more than about 1% w/wof the corresponding (−)-enantiomer.
 4. The method of claim 1, whereinthe anxiety disorder is selected from the group consisting of PanicDisorder, Panic Attack, Agoraphobia, Generalized Anxiety Disorder,Obsessive-Compulsive Disorders, Phobic Disorders and Post-TraumaticStress Disorders.
 5. The method of claim 2, wherein the anxiety disorderis selected from the group consisting of Panic Disorder, Panic Attack,Agoraphobia, Generalized Anxiety Disorder, Obsessive-CompulsiveDisorders, Phobic Disorders and Post-Traumatic Stress Disorders.
 6. Themethod of claim 3, wherein the anxiety disorder is selected from thegroup consisting of Panic Disorder, Panic Attack, Agoraphobia,Generalized Anxiety Disorder, Obsessive-Compulsive Disorders, PhobicDisorders and Post-Traumatic Stress Disorders.
 7. A method for treatingan eating disorder in a patient, comprising administering to a patientin need of such treatment an effective amount of(+)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane.
 8. The methodaccording to claim 7, wherein the(+)-1-(3,4Dichlorophenyl)-3-azabicyclo[3.1.0]hexane or pharmaceuticallyacceptable salt thereof has no more than about 2% w/w of thecorresponding (−)-enantiomer.
 9. The method according to claim 7,wherein the (+)-1-(3,4Dichlorophenyl)-3-azabicyclo[3.1.0]hexane orpharmaceutically acceptable salt thereof has no more than about 1% w/wof the corresponding (−)-enantiomer.
 10. The method of claim 7, whereinthe eating disorder is selected from the group consisting of AnorexiaNervosa, Binge-Eating Disorder, Bulimia Nervosa—Nonpurging Type andBulimia Nervosa—Purging Type.
 11. The method of claim 8, wherein theeating disorder is selected from the group consisting of AnorexiaNervosa, Binge-Eating Disorder; Bulimia Nervosa—Nonpurging Type andBulimia Nervosa—Purging Type.
 12. The method of claim 9, wherein theeating disorder is selected from the group consisting of AnorexiaNervosa, Binge-Eating Disorder, Bulimia Nervosa—Nonpurging Type andBulimia Nervosa—Purging Type.
 13. A method for treating a urinaryincontinence disorder in a patient, comprising administering to apatient in need of such treatment an effective amount of(+)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof, each being substantially freeof its corresponding (−)-enantiomer.
 14. The method according to claim13, wherein the (+)-1-(3,4Dichlorophenyl)-3-azabicyclo[3.1.0]hexane orpharmaceutically acceptable salt thereof has no more than about 2% w/wof the corresponding (−)-enantiomer.
 15. The method according to claim13, wherein the (+)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane orpharmaceutically acceptable salt thereof has no more than about 1% w/wof the corresponding (−)-enantiomer.
 16. The method of claim 13, whereinthe urinary incontinence disorder is selected from the group consistingof Urge Incontinence; Stress Incontinence, Overflow Incontinence,Functional Incontinence, Neurogenic Incontinence and Post-ProstatectomyIncontinence.
 17. The method of claim 14, wherein the urinaryincontinence disorder is selected from the group consisting of UrgeIncontinence, Stress Incontinence, Overflow Incontinence, FunctionalIncontinence, Neurogenic Incontinence and Post-ProstatectomyIncontinence.
 18. The method of claim 15, wherein the urinaryincontinence disorder is selected from the group consisting of UrgeIncontinence, Stress Incontinence, Overflow Incontinence, FunctionalIncontinence, Neurogenic Incontinence and Post-ProstatectomyIncontinence.